The New Paradigm for Proarrhythmia Assessment without the ...

The New Paradigm for Proarrhythmia

Assessment Without the TQT Study

Philip Sager, MD, FACC, FAHA, FHRS

Pharmaceutical/Device Consultant

Consulting Professor of Medicine

Stanford University School of Medicine

Chair, Scientific Programs Committee,

Cardiac Safety Research Consortium

[email protected]

• Drs. Stockbridge, Gintant, Pettit

• FDA

• EMA

• PMDA

• Health Canada

• CSRC

• HESI

• SPS

• In Silico Modelers

• Pharmaceutical and Device Companies

• CRO’s

• Numerous Academic Groups

Collaborators

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QT Prolonged/Drug-Induced Torsade

• QT prolongation/TdP – single most common cause of withdrawal or restriction on marketed drugs

• This has resulted in the need for regulatory guidance

• TdP rarely observed during clinical development

• Focus on surrogates- HERG and QTc testing

– QTc- sensitive but not very specific

4

S7B: Nonclinical Testing Strategy

Chemical/Pharma-

cological Class

Integrated Risk

AssessmentFollow-up

studies

None Weak Strong

Evidence of Risk

Other nonclinical and

clinical information

In vivo QT

assayIn vitro IKr

assay*

*The hERG (gene for Kv11.1 alpha subunit of IKr)) related current is used

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Consequences: Compound with QT effect

Consequences of developing a compound with QT

effect

• Significant development burden

• Increased perceived risk = increased burden

to demonstrate benefit

• Increased costs

• Delays in filing and/or approval

• Label warnings and competitive implications

• Licensing/partnering issues

• Often leads to termination of development

ICH E14- increase in QTc~5m is “positive

Torsadogenic Drugs

• ICH E14/S&B have resulted in no drugs with unrecognized

risk being approved

• Success!

• Negative impact on drug development

– Premature discontinuation due to hERG or QT “signal”

• (Inaccurate) perception of risk, development burden,

costs, labeling

• Some potentially good compounds never get evaluated

in humans

– Drug development in specific areas- CNS

– Many drugs with QT labeling are unlikely proarrhythmic

Ventricular Repolarization

QT Prolongation: Dissociation from TdP

• Sodium Pentobarbital - Prolongs QT but no TdP- Inhibits Ikr, Iks, and late INa

• Amiodarone- TdP very rare- Inhibits Ikr, Iks, late INa, and Ica

• Verapamil- Inhibits IKr but also Ca influx

• Ranolazine- Prolongs QT but no TdP- Inhibits late INa, Ikr, and INaCa

QT Prolongation: Dissociation from TdP

• Sodium Pentobarbital - Prolongs QT but no TdP- Inhibits Ikr, Iks, and late INa

- No EAD’s, reduces dispersion

• Amiodarone- TdP very rare- Inhibits Ikr, Iks, late INa, and ICa

- No EAD’s, reduces dispersion

• Verapamil- Inhibits IKr but also Ca influx- No QT prolongation or TdP

• Ranolazine- Prolongs QT but no TdP- Inhibits late INa, Ikr, and INaCa

- No EAD’s, reduces dispersion; - Suppresses E4031 induced TdP

Thus QTc Prolongation need not cause TdP

Issues

• QT prolongation = Proarrhythmia

• HERG block = Proarrhythmia

• Negative impact on drug development

• New paradigm- based on our deep mechanistic understanding of TdP

New Paradigm

Might a new cardiac safety paradigm focused on non-clinical measurement of proarrhythmia proclivity:

Focus on the real issue: Proarrhythmia• Reduce the premature termination of drugs with

favourable benefit:risk profiles

• Make drug development more efficient

– Move the bulk of proarrhythmic assessment to the discovery phase

– Use the assays to potentially guide candidate selection

– Obviate the TQT study

• Enhance the accuracy with which existing and/or new drugs are labelled relative to actual proarrhythmic risks

(American Heart J 2014 (In Press (available on-line)

• Proarrhythmic risk can be determined by pre-

clinical assessments

• Proclivity to develop EAD’s• Ionic Currents

• in silico modeling • Cell-Based Approach

• Focus on high throughput approaches

• ECG Phase 1 Assessment

CiPA Paradigm | CSRC Annual Meeting | Dec. 12, 2013 | Copyright © 2013 AbbVie 15

Background: Proarrhythmic Vulnerability and Early Afterdepolarizations (EAD’s)

We understand the mechanism!

Proarrhythmic vulnerability linkedto impairment of repolarization and repolarization instability manifest culminating in early afterdepolarizations (EAD’s)

- EAD’s are triggers for Torsades de Pointes arrhythmia

- Ease of EAD induction reflects proarrhythmic vulnerability

- Provide means of ranking proarrhythmic potential


Assays and Approaches Considered for Comprehensive Assay (In Order of Complexity, Integration)

Approach Description

QSARModels describing relationship between molecular structural

features and properties or activities at given

pharmacological/toxicological endpointReceptor Affinity

Assays

Typically competitive binding studies to ion channels

Single Channel

Recording

Highly detailed measure of current

through a single ionic channel

Macroscopic Ionic

Currents

Detailed analysis of drug effects on

functional cardiac currents; widely accepted

Isolated Cardiac

Myocytes

Cardiocytes of human origin more likely to reflect native phys-

iology; availability of stem-cell cardiocytes vs. tissues

In vitro/in vivo

proarrhythmia

Tissues/organs or whole animal models

mimicking enhanced proarrhythmia risk

Computer Models

of Cardiac Myocytes

Reconstruction of electrical activity of ventricular myocytes

from channel effects (delayed repolarization and EAD's)

Whole Heart

Computer Models

Reconstruction of ECG and drug effects

(incorporates individual channels and action potential studies)


CiPA: Two Component Proposal

- Complementary approaches

- Not designed to reproduce arrhythmia

Effects on MultipleCardiac Currents

(Voltage Clamp Studies)

Reconstruction of Cellular Electrophysiology

(In Silico Studies)

+

Effects on Human Ventricular Myocytes

(In Vitro Studies)

Ionic Currents / In Silico Myocyte-Based Based Approach Approach

Define a gradation of risk instead of a binary approach


Core In Vitro Strategy. Voltage Clamp Studies

Ionic Currents

• Voltage clamp studies – Effects on cardiac currents

– Human channels in in n heterologous expression systems

– Establish best practices, standardizationacross assays, laboratories

– Inhibition of current, ? Use dependency

• Higher throughput automated patch platforms- Efficiently determine basic characteristics of

drug effects on currents for in silico reconstruction


Likely Candidate Currents

- iKr (hERG) – delayed ventricular repolarization

- INafast (Nav1.5) –excitability, conduction

- INalate (Nav1.5) –repolarization, mitigate hERG block

- ICaL (Cav1.2) –A-V conduction, mitigate hERG block

- IKs (KvLQT1-minK) –delayed ventricular repolarization


Core in silico Strategy: Reconstruction of the Cardiac Action Potential

Silico Reconstruction of Action Potentials

- Global effects on repolarization based on multiple ion channel effects

- Approach based on link between delayed repolarization supporting early afterdepolarizations (EAD’s) and TdP


Core In vitro Strategy: Human Cardiomyocytes

Electrophysiologic studies:- Human stem-cell derived ventricular cardiomyocytes;

well characterized, physiologic recording conditions

• - Action potential studies, focus on repolarization (duration, early afterdepolarizations, cellular integration)

- Reproducibility essential, robust validation

- Confirm drug effects from voltage clamp/in silico reconstructions


Stem-Cell Derived Myocytes: Possible Experimental Approach

Field Potential Measures (Microelectrode Array Techniques)

E-4031: Concentration-dependent Block of iKr Delays Repolarization, Provokes EAD’s

Nifedipine: Concentration-dependent Block of IcaL Speeds Repolarization


Stem-Cell Derived Myocytes: Possible Experimental Approach

Perforated patch method

Ma J Am J Physiol HeartCirc Physiol 301: H2006–H2017, 2011

? Determine excitability during Phase 3


• New technology that is evolving

• Desire to have as homogenous a population of adult cardiomyocytes as possible

• Evolving maturation and changes in EP properties over time

• “Standardization” across laboratories and stem cell sourcing

• Determination of appropriate drug-induced metrics indicating proarrhythmia proclivity

Human IPS-Derived Stem Cells


Approach based on

a) mechanistic understanding, integrating effects onmultiple ion currents with in silico reconstruction

b) confirmation in human ventricular myocyte-based assay

- Not typical preclinical assay based on binary discrimination in complex, integrated (poorly understood) biological system

- Need input from safety pharmacologists, electrophysiologists, computational modelers, cell biologists, regulators

First Steps: Seek Input, Establish Workstreams (ongoing)

Summary and Paths Forward: CiPA Proposal


What It Will Do: - Standardize in vitro assays (used to characterize

drug effects) and in silico modeling of drug effects

- Define role of human cardiomyocytes to inform on proarrhythmic potential of drugs

- Provide proarrhythmic ranking based on calibration efforts with agreed-upon standards - Not a binary approach

What It Will Not Do:- Maintain status-quo for an imperfect surrogate marker of proarrhythmia

Comprehensive In Vitro ProArrhythmia Assay (CiPA)

ILSI Health and

Environmental Sciences

Institute

CIPA PROCESS

• Work streams

– In Silico, Ion Channel, Myocyte, Regulatory, Steering Team

• Topical area leads

• Coordination and cross-stream interaction


In Silico – model design, execution, feedback and vetting Tom Colatsky ([email protected])

Ion Channel – channel selection, protocol development, novel data generation to test model; Syril Petit ([email protected])

Stem Cell Myocyte – protocols, platforms and validation; ([email protected])

Regulatory – model design and validation compound selection, arrhythmia metrics, ECG assessment ([email protected])

Steering Team – Coordination and integration

Work Streams

Norman Stockbridge, FDA: [email protected] Pierson (HESI): Jennifer Pierson [email protected]

ILSI Health and


Institute30

CIPA Steering Team

Name Organization Representing Work Stream Represented

Norman Stockbridge FDA US Regulators All

Tom Colatsky FDA US Regulators In Silico Work Stream

Gary Gintant AbbVie Pharm/Non-clinical community All

Hugo Vargas Amgen Pharma/SPS Ion Channel Work Stream

Derek Leishman Lilly Pharma/SPS Ion Channel Work Stream

Jean-Pierre Valentin AZ Pharma/Non-clinical community Ion Channel Work Stream, Regulatory Work Stream

Philip Sager CSRC Clinical Community Regulatory Work Stream, Ion Channel Work Stream

Jiwen Zhang GE Healthcare Pharma/Stem Cell Community Myocyte Work Stream

Krishna Prasad EMA Non-US Regulators Regulatory Work Stream

Colette Strnadova Health Canada Non-US Regulators Regulatory Work Stream

Natalia Trayanova Johns Hopkins Modeling Community In Silico Work Stream

Syril Pettit HESI HESI Cardiac Safety Committee All

Jennifer Pierson HESI HESI Cardiac Safety Committee All

To Be Determined PMDA Japanese Regulators Regulatory Work Stream

ILSI Health and


Institute31

CIPA Steering Team

Name Organization Representing Work Stream Represented

Norman Stockbridge FDA US Regulators All

Tom Colatsky FDA US Regulators In Silico Work Stream

Gary Gintant AbbVie Pharm/Non-clinical community All

Hugo Vargas Amgen Pharma/SPS Ion Channel Work Stream

Derek Leishman Lilly Pharma/SPS Ion Channel Work Stream

Jean-Pierre Valentin AZ Pharma/Non-clinical community Ion Channel Work Stream, Regulatory Work Stream

Philip Sager CSRC Clinical Community Regulatory Work Stream, Ion Channel Work Stream

Jiwen Zhang GE Healthcare Pharma/Stem Cell Community Myocyte Work Stream

Krishna Prasad EMA Non-US Regulators Regulatory Work Stream

Colette Strnadova Health Canada Non-US Regulators Regulatory Work Stream

Natalia Trayanova Johns Hopkins Modeling Community In Silico Work Stream

Syril Pettit HESI HESI Cardiac Safety Committee All

Jennifer Pierson HESI HESI Cardiac Safety Committee All

To Be Determined PMDA Japanese Regulators Regulatory Work Stream


• Exciting potential evolution in CV Arrhythmia assessment

• Potential to change current approaches with positive impact on drug development

• Can concepts be extended to other areas?

• Many opportunities for those interested in contributing to become involved

Summary


Galapagosization

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Thank you

Philip Sager, MD, FACC, [email protected] 1-650.450.7477

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